Stress- und Depressionsforschung

The main research focus of the Hasler group is molecular neuroimaging of the glutamate and GABA neurotransmitter systems in affective disorders, including depression and bipolar disorder. We are building up our research on our previous work on reduced glutamate and GABA concentrations in the prefrontal cortex of depressed individuals. Currently, we are studying the effects of ketamine in unipolar and bipolar depression. Ketamine is antidepressant with rapid and robust effects, targeting the glutamate system. In a large cohort study, we measure glutamate, glutamine and GABA in the general population as correlate of depression vulnerability and as predictors of affective disorders. We use multimodal imaging to examine prefrontal glutamate concentrations using MRI, fMRI and in combination with PET imaging on the metabotropic glutamate receptor 5 in bipolar depression.

Projects

• Glutamatergic system

  All conventional antidepressant drugs affect the neurotransmitters serotonin and norepinephrine. However, recent studies show that drugs affecting the messenger glutamate demonstrate a stronger and faster effect compared to conventional drugs. In a series of studies, we have demonstrated that the glutamate system is changed in patients with depression. These changes are believed to be the reason for the strong effect of glutamate drugs. In particular, Ketamine shows a strong antidepressant effect. Therefore, we started to use Ketamine at our ambulatory clinic (Bolligenstrasse) for the treatment of severe depression using specific treatment guidelines. The aim of our research is to evaluate the efficacy and safety of this treatment. In addition, we use magnetic resonance spectroscopy to assess glutamate, glutamine and GABA in a community based-cohort study, and apply multimodal imaging on the glutamate system (glutamate, glutamine, mGluR5 PET) to elucidate the pathogenesis of bipolar depression and early phases of psychosis.

• Paralysis of the frown lines

  In recent years, three randomized, placebo-controlled studies have found a surprisingly large antidepressant effect in the paralysis of frown lines of the forehead by Botulinum toxin A (Botox) in depression. The average response rate was 54 percent. We plan to offer this treatment at our ambulatory clinic (Bolligenstrasse). In a scientific study, we want to determine why this therapy is so effective. The paralysis may lead to a suppression of negative emotions. We plan to investigate this through psychological experiments and EEG measurements. Further, the inhibited expression may improve social interactions. We plan to investigate this with regular, short smartphone-surveys. We will also consider whether the aesthetic effect strengthens the self-esteem of the depressive patient. The findings of this study will contribute to an optimal use of botulinum toxin A in depression.

• Impartial understanding of social behavior

  Recent studies regarding the career outcomes of depressed people show that disruptive social behavior can be more decisive than classic depressive symptoms such as the depressive mood and sadness that usually occur only temporarily. Until now, there have been no simple, effective  methods to reliably measure social behavior. Hence, the knowledge of the treatment of social behavior disorders is very low. In a series of studies using simple experiments based on behavioural economics, we have examined the social behaviors of depressive patients and patients with personality disorders. We have shown that, even after the amelioration of depressive symptoms, patients tend to avoid competitive situations. However, questionnairs have shown that this avoidance correlates with depressive symptoms. In follow-up studies, we aim to make our behavioural social-measurement methods more accurate by additionally using brain imaging techniques. Our approch is highly innovative, since investigation of neural networks involved in competition avoidance of patients with depression has not been attempted before. Our final aim is developing therapeutic strategies to treat competition avoidance, so that the patients will increase their chances for better employment chances and competitive jobs.

• Testing of anti-stigma campaigns

  The majority of the population have a rather negative opinion about depression, leading to shame in people who suffer depression. This leads to inadequate treatment and difficulties during job-related reintegration. The stigma against depression is often implicit (an unconscious, automatic behavior). Previous anti-stigma campaigns did not show any improvement. To the contrary, they may have led to worsening outcomes. To clarify the effects of anti-stigma campaigns, we develop methods to measure implicit effects. This methodology will allow us to psychologically test campaigns before their general application.

• Biomarkers

  Leading experts agree that the discovery of biomarkers for mental disorders is of paramount importance to promote psychiatric research. Biomarkers are objective diagnostic indicators that improve diagnoses and facilitate the choice of therapies. Today different medications, psychotherapies, and treatment settings must be tested until the optimal therapy is found. Biomarkers help shorten this therapy-setting-process. Furthermore, biomarkers may help to develop new therapies that are specifically tailored to disease processes.
   
  The greatest scientific success of our group in recent years has been the discovery of a glutamate receptor, mGluR5, as a biomarker for nicotine dependence. Using emission tomography, we showed that the amount of this receptor is 30 percent lower in a smoker’s brain. After more than five years of abstinence, the level of the receptor normalizes. A slow recovery of the receptor predicts a high recidivism rate. These findings inspired Novartis to investigate drugs targeting mGluR5 for addiction therapy.
   
  In a series of studies, we have developed biomarkers that predict responses to conventional antidepressants. Our method allows researchers to determine whether a serotonin deficiency, a norepinephrine deficiency, or both are present. We were able to show the significance of these biomarkers in depression and in bulimia.
   
  In an ongoing study, we are measuring a possible lack of dopamine as a biomarker for schizophrenia. The development of this biomarker will allow to selectively adjust antipsychotic drugs throughout the disease process.
   
  In a large project (in collaboration with the University of Zurich and the Epigenetics Laboratory at the Mount Sinai School of Medicine in New York), we evaluate epigenetic alterations as biomarkers for mental disorders in the general population. Epigenetics refers to the modification of genes by environmental factors. Such markers allow us to better understand the role of social and genetic factors in the development of mental disorders. The results may help uncover efficient preventive and therapeutic measures.

• Gut Brain Axis

  In recent decades, basic and clinical research has found increasing evidence that the gastrointestinal tract and nutrition may play an important role in neurological and psychiatric diseases.

  The connection between the gastrointestinal tract and the brain is also called the gut-brain axis. It consists essentially of the following parts:

  • Vagus nerve: the most important function of the vagus nerve is afferent, meaning that it transmits information from the internal organs, mainly from the intestines. This suggests that the gut is an important sources of sensory information to the brain. 
  • Stress Nerve (Sympathetic Nerve): Through this nerve, the brain can curb intestinal activity, as is necessary under acute stress.
  • Gut hormones: the gut has its own nervous system, with more than thirty neurotransmitters and more nerve cells than the spine. Dozens of hormones and peptides released into the bloodstream by the gut nervous system cross the blood-brain barrier and have multiple neuropsychological effects on the brain.
  • Immune system: 80% of the immune system is located around the intestine. The gut immune system is connected to the brain immune system via the vagus nerve, lymph, cytokines and other factors.
  • Gut Bacteria: The gut is the main location of the human microbiome. Intestinal bacteria, also known as gut flora, have far-reaching effects on many bodily functions and the brain.

  For all these reasons, the brain-gut axis is becoming increasingly important as a therapeutic target for neurological and neuropsychiatric disorders such as stroke, epilepsy, neurodegenerative diseases, autism, depression, and post-traumatic stress disorder. Current treatment options for modulating the brain-gut axis include dietary changes, fasting, vagus nerve stimulation, meditation techniques, hypnotherapy, and probiotics. Drug therapies that affect the axis, such as antibiotics, psychedelics, and ketamine are currently being investigated. 

  My research group at UNIFR is investigating new diagnostic methods for disorders of the gut-brain axis, as well as new therapeutic options that target the axis, and evaluating their clinical utility. There is a collaboration with the neurological hospital Cereneo/Lake Lucerne Institute regarding this research project.

• Psychedelics and neuroplasticity
  Neuroplasticity refers to the brain’s ability to grow, change, and reorganize itself. In some psychological disorders, such as depression and anxiety, neuroplasticity becomes impaired in specific neural circuits. This has led to the theory that restoring neuroplasticity in those circuits might help the brain become “unstuck” from the negative patterns of thought and behavior that characterize mood disorders. Interventions which enhance neuroplasticity may also have the potential to treat neurodegenerative disorders, stroke, and other disorders associated with rigid patterns of thought and behavior.

  Recent research suggests that psychedelic drugs, when given in a safe and supportive setting, may be highly effective treatments for depression, anxiety, and substance use disorders. Additionally, animal studies have shown that psychedelics rapidly enhance cortical plasticity. Our lab is interested in whether a single dose of LSD also opens a “window of plasticity” in humans – and if so, what this means for cognition, behavior, and mental health.